Asymmetric synthesis of propargylic alcohols via aldol reaction of aldehydes with ynals promoted by prolinol ether-transition metal-Bronsted acid cooperative catalysis

Article abstract of DOI:10.1039/c3sc51027a

A catalytic and highly stereoselective entry to propargylic alcohols and products derived thereof is reported based on an unprecedented cross-aldol coupling between unmodified aldehydes and ynals. The method requires an amine-metal salt-Bronsted acid ternary catalyst system and implies synergistic activation of the donor aldehyde via enamine and of the acceptor carbonyl via unique and reversible metal-alkyne complexation. Specifically, by using a combined α,α-dialkylprolinol silyl ether-CuI-PhCO ₂H catalyst system, remarkably high levels of diastereo- and enantioselectivity (anti/syn up to >20:1, ee up to >99%) are achieved.

Full text of DOI:10.1039/c3sc51027a

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Asymmetric synthesis of propargylic alcohols via aldol
reaction of aldehydes with ynals promoted by prolinol
ether–transition metal–Brønsted acid cooperative
catalysis†
Cite this: DOI: 10.1039/c3sc51027a
a
b
a
a
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´
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Enrique Gomez-Bengoa, Jesus M. Garcıa, Sandra Jimenez, Irati Lapuerta,‡
a
b
a
b
a
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´
~
Antonia Mielgo, Jose M. Odriozola, Itziar Otazo,‡ Jesus Razkin, Inaki Urruzuno,
Silvia Vera,‡ Mikel Oiarbide and Claudio Palomo
a
a
a
*
A catalytic and highly stereoselective entry to propargylic alcohols and products derived thereof is reported
based on an unprecedented cross-aldol coupling between unmodified aldehydes and ynals. The method
requires an amine–metal salt–Brønsted acid ternary catalyst system and implies synergistic activation of
the donor aldehyde via enamine and of the acceptor carbonyl via unique and reversible metal–alkyne
complexation. Specifically, by using a combined a,a-dialkylprolinol silyl ether–CuI–PhCO2H catalyst
system, remarkably high levels of diastereo- and enantioselectivity (anti/syn up to >20 : 1, ee up to
>99%) are achieved.
Received 17th April 2013
Accepted 20th May 2013
DOI: 10.1039/c3sc51027a
www.rsc.org/chemicalscience
realizing such a transformation in a catalytic and asymmetric
manner from readily available substrates remains poorly
Introduction
Propargylic alcohols constitute small but densely functionalized
units that, owing to the rich chemistry of the carbon–carbon
triple bond, may serve as building blocks in the construction of
molecular complexity.1 Despite their synthetic value, there are
few catalytic entries to propargylic alcohols of stereodened
structure, namely: (a) the reduction of ynones, (b) the addition
of terminal alkynes to aldehydes, and (c) the 1,2-addition of
addressed, if at all. Here we report a cross aldol reaction
between aldehydes and ynals promoted by prolinol ether–
transition metal–Brønsted acid cooperative catalysis that
enables a straightforward and highly stereocontrolled synthesis
of functionalized propargylic alcohols.
nucleophiles to a,b-ynals (Fig. 1).2 Although the rst two Results and discussion
methods have been studied extensively, efforts for exploring the
latter approach have been essentially limited to the use of
organometallic reagents, which usually allow for the generation
of a sole stereocenter and do not readily permit concomitant
introduction of additional functionality.
Background and reaction design
Despite the fact that the aldol reaction stands among the most
amply investigated chemical transformations, examples of
The aldol addition3 of an enolate or equivalent to an a,b-ynal
can be viewed as an attractive means for accessing propargylic
alcohols because two contiguous stereocenters may be gener-
ated at once, with concomitant formation of a new carbon–
carbon bond between them, and a b-carbonyl group is also
installed, all under rather mild reaction conditions. However,
a
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´
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Departamento de Quımica Organica I, Facultad de Quımica, Universidad del Paıs
´
Vasco UPV/EHU, Apdo. 1072, 20080 San Sebastian, Spain. E-mail: claudio.
palomo@ehu.es
b
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Departamento de Quımica Aplicada, Universidad Publica de Navarra, Campus de
´
Arrosadıa, 31006 Pamplona, Spain
† Electronic supplementary information (ESI) available: Experimental procedures,
structural proofs, and spectral data for all new compounds are provided. See DOI:
10.1039/c3sc51027a
‡ These authors contributed equally to this work.
Fig. 1 Fundamental routes to propargylic alcohols and our strategy.
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Table 1 Catalysts screening for the direct cross aldol reaction between 1A and 2aa
Entry
Amine
MLn
Acid
Conv. (%)
Yieldb (%)
anti : sync
eed (%)
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
4
5
6
6
7
—
CuI
—
CuI
Cu(OAc)2
Ph3PAuCl
Rh2(OAc)4
Rh2(OAc)4
AgOAc
Cu(OAc)2
—
—
—
NR
40
65
>95
>95
>95
45
>95
>95
74
—
—
—
71
72
73
—
70
68
55
—
48
—
—
6 : 1
7 : 1
—
98
94
99
99
97
—
97
99
97
97
99
98
PhCO2H
PhCO2H
PhCO2H
PhCO2H
—
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
>20 : 1
>20 : 1
19 : 1
—
>20 : 1
>20 : 1
2 : 1
1.5 : 1
1.5 : 1
2.5 : 1
9
10
11
12
13
60
73
33
CuI
CuI
a
Reactions conducted on a 0.5 mmol scale in 0.5 mL of THF (mol ratio of 1/2/3/MLn/acid, 3 : 1 : 0.2 : 0.1 : 0.2). b Isolated yield of cross aldol product
aer reduction to diol. c Determined by 1H NMR, >20 : 1 means the minor diastereomer was not observed in the 300 MHz 1H NMR. d ee of major
diastereomer determined by chiral HPLC. NR: no reaction observed.
enantioselective aldol reactions involving a,b-ynals have been eventual catalysts inactivation via acid–base self-quenching,13 if
seldom reported in literature,4 and the problem of reaction successful, a new entry for the stereoselective construction of
stereoselectivity for these types of substrates, particularly syn/ functionalized propargylic alcohols would emerge.
anti diastereoselectivity,5 has remained unsolved.6 The only
systematic study is that of Carreira et al., who described the Ti-
catalyzed acetate-aldol addition reaction of silyl ketene acetals
Catalysts screening and reaction optimization
with ynals.7 The propargylic aldol adducts were obtained in high To validate the above hypothesis, we set out to study the reac-
enantioselectivity, but no examples involving a-substituted tion of hydrocinnamaldehyde 1A and propargyl aldehyde 2a in
enolate equivalents were reported. Whilst the specic reasons the presence of prolinol ether 4, an effective chiral catalyst
that make ynals particularly difficult aldehyde substrates for previously developed by us for the enantioselective Mannich
reaction stereocontrol remain intriguing, we speculated that reactions of aldehydes with alkynyl imines.14 Initial experi-
their linear shape might constitute a detrimental structural ments carried out in parallel with 4 as the only catalyst (Table 1,
feature. Indeed, the use of preformed ynal–hexacarbonylcobalt entry 1) or with a combination of 4 and a carbophilic metal salt,
complexes, instead of naked ynals, has been shown to signi- such as CuI (entry 2), showed a promising cooperative effect.
cantly increase the diastereoselectivity of aldol reactions with Thus while no reaction was observed at all with only 4, in the
silyl enol ethers, apparently because of the increased bulk of the presence of CuI cocatalyst around 40% reaction conversion was
ynal–metal complex.8
measured aer 20 h at À60 ꢀC. A similar cooperative effect was
Accordingly, we sought to establish a general and highly also observed when 4 was employed in combination with a
stereoselective direct aldol reaction of ynals based on a novel Brønsted acid cocatalyst (entry 3).15 In both cases diol 3Aa was
cooperative catalysis featuring the following reaction design produced with a suboptimal anti : syn ratio, typically 7 : 1,
elements: activation of donor carbonyl (aldehyde) via chiral albeit this selectivity is superior to that previously reported for
enamine catalysis9 and concomitant activation of acceptor direct aldol reactions involving ynals, vide supra. At this point
carbonyl (ynal) via in situ and reversible ynal–metal complexa- our feeling was that while both the metal salt and the Brønsted
tion. While the realization of this idea faces considerable acid seem to provoke similar catalytic effects, their modes of
challenges, specically the complications inherent in the action might be distinct and therefore both cocatalysts may
aldehyde–aldehyde cross aldol reaction10–12 and the problem of complement each other rather than cancel one another.
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Table 2 Scope of the catalytic cross aldol reaction of ynalsa
remarkably, anti-isomer was formed almost exclusively and in
99% ee. Consequently, these results indicated that each cata-
lyst component, namely amine, metal salt, and Brønsted acid is
crucial for the optimum reaction outcome. We also observed
that reaction temperature is critical to suppress aldehyde self-
aldolization; at À40 ꢀC or temperatures above, homodimeri-
zation occurred to varying extents regardless of the presence or
absence of the metal cocatalyst. On the other hand, experi-
ments carried out with metal cocatalysts other than copper,
such as Au(I), Rh(II) or Ag(I) derivatives (entries 6, 8, 9), clearly
revealed that this cooperative effect is a general attribute of
other carbophilic metal salts. In each case the anti aldol was
formed as essentially the sole isomer with very high enantio-
selectivity. As evidenced by these results, a distinguishing
feature of the present synergistic transition metal–organo-
catalysis strategy with alkynyl substrates is that, contrary to
most previous developments, no reaction at the carbon–carbon
triple bond occurred.16 To investigate the role played by the
metal counterion in the ternary catalyst system, subsequent
experiments were carried out using CuOTf and Cu(OTf)2,
respectively, in place of CuI and Cu(OAc)2. Under these
conditions, no reaction occurred, indicating that the Lewis acid
character of the metal salt is important for reactivity. Further
experiments eventually showed that while the 4–InCl3–PhCO2H
catalyst system achieved some activity (30% conversion,
anti : syn 2 : 1), other systems containing Zn(OTf)2, FeCl3,
AuCl3, or YbCl3 as the metal cocatalyst were totally ineffective
for this reaction. Finally, the importance of amine catalyst 4
was assessed by performing reactions under otherwise similar
conditions but in the presence of the standard pyrrolidine
catalysts 5–7.17 As the results in the table show, in these latter
cases both reactivity and diastereoselectivity were eroded
(entries 10–13), thus demonstrating that while possessing a
closely related structure, the aryl to alkyl shi in the
amine catalyst side chain may in certain situations be
highly effective.18
Reaction scope and adducts application
With the optimized conditions in hand we explored the reac-
tion scope using a representative selection of enolizable alde-
hydes and ynals. Adducts were isolated as the corresponding
diols or acetals, respectively (Table 2). Not only ynals with
hydrocarbon (phenyl, cyclic alkyl, and acyclic alkyl) pendant
chain, but also those bearing a silyl, ether, acetal, chloro, or
thiophene groups were all tolerated almost equally. Signi-
cantly, no N-alkylation of the amine catalyst using chloro-ynal
2j, nor metal catalyst inactivation using thiophene ynal 2k, was
observed. With respect to the nature of the donor aldehyde
component, short alkyl chain aldehydes such as propanal,
longer chain aldehydes such as heptanal or hydro-
cinnamaldehyde, or even aldehydes bearing side chains with
functional groups such as alkene, carbamate, ester, ether, and
a
Reactions conducted on a 0.5 mmol scale in 0.5 mL of THF (mol ratio
b
1 : 2 : 3 : BA : CuI, 1.5–1.2 : 1 : 0.2 : 0.2 : 0.1). Combined yield of the
c
anti : syn cross aldol mixture aer chromatography. Determined by
1H NMR and corroborated by HPLC; data in parentheses refer to
reactions carried out with benzoic acid as the sole cocatalyst.
d
e
Determined by chiral HPLC. No reaction observed using CuI as the
sole cocatalyst.
Indeed, to our delight, the reaction carried out in the presence acetal, participated satisfactorily, giving high diaster-
of 4, CuI or Cu(OAc)2 (10 mol%), and benzoic acid (20 mol%) eoselectivities and generally excellent ee’s. As the results in
(entries 4 and 5) not only was complete aer 16–20 hours at Table 2 show, ynals with alkyl substituents provided, with one
ꢀ
À60 C, providing 3Aa in about 70% isolated yield, but most exception (3Bl), the addition products in dr's greater than 13 : 1
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and ee's in the range of 94–99%, whereas ynals with aryl
substituents generally gave products with dr's from 7 : 1 to
10 : 1 and slightly lower ee's, typically 92–94%. On the other
hand, experiments showed once again that the three compo-
nents of the catalyst system, i.e. amine, metal salt and Brønsted
acid, were necessary to achieve good levels of reactivity and
stereoselectivity. Thus, for compounds 8Aa, 3Ae, 3De and 3Hc,
in the absence of either benzoic acid or CuI cocatalyst, inferior
(typically 6 : 1) anti : syn selectivity or lack of reactivity was
observed. Of practical interest is also the fact that under opti-
Scheme 1 Chemoselective cross aldol reaction of dialdehyde 9.
ꢀ
mized conditions (THF, À60 C) neither a syringe pump tech-
nique to preclude aldehyde homodimerization,10 nor a large
excess of the donor aldehyde with respect to the acceptor
(typical mol ratio 1.5–1.2 to 1, see Table 2) were necessary,11
a
relevant consideration when expensive aldehydes or aldehydes
requiring multi-step synthesis are involved. It is worth noting
that under the studied conditions, products from an eventual
1,4-addition were not formed to any signicant extent. Thus,
the present catalyst system allows straightforward exploitation
of the ynal 1,2-reactivity pattern at the expense of the 1,4-
addition pathway, which is generally exhibited by these alde-
hydes upon iminium activation catalysis.19
Interestingly, our reaction design is applicable to more
complex scenarios where manifold inter- and intramolecular
aldol pathways may compete. For instance (Scheme 1), treat-
ment of 9 and phenylpropargyl aldehyde 2f with catalyst 4,
benzoic acid and CuI in THF at À60 ꢀC, furnished cross-aldol 10
as essentially a single isomer, which was isolated as acetal 8Gf
in 52% yield and 99% ee. Given the tendency of dialdehydes
Scheme 2 Primary utility of propargylic adducts 3 or 8.
such as
9 to react intramolecularly leading to 5- and
6-membered carbocycles,20 it is remarkable that under the
above conditions the intramolecular aldol reaction product 11
was formed in only minute amounts (<10%).
The obtained aldol adducts are interesting building-blocks
in their own right, but could also be easily transformed, as
shown in Scheme 2, into their saturated analogs. For instance,
catalytic hydrogenation of the triple bond in adducts 3Ae, 3Bf,
3Ca and 3De yielded the corresponding products 12–15, which
are products from a formal cross-aldol reaction between two
dissimilar aliphatic aldehydes. Importantly, since the discovery
of the amine-catalyzed direct intermolecular aldol reaction,21 no
direct aldol cross-coupling method is currently available for
such a type of linear chain enolizable aldehydes.22,23 Alterna-
tively, controlled reduction of the triple bond in adducts 8 by
treatment with Red-Al furnished 16–18 in high yields. The latter
products are elusive and difficult to obtain through direct aldol
reaction between aldehydes and the corresponding a,b-unsat-
urated aldehyde because of the prevalence of the enamine/
iminium mediated 1,4-addition.24
Fig. 2 Selected products synthesized from aldol adducts 3 or 8.
Additional synthetic utility of the present catalytic cross-
aldol methodology is illustrated in the transformation of the
resulting propargylic adducts into a variety of structural
motifs bearing two or more stereocenters, such as those
depicted in Fig. 2.25 This realization is of particular interest in
that known methods for the enantioselective synthesis of
propargylic alcohols, vide supra, may only generate a single
stereocenter.1c,2
Fig. 3 Approaching geometries that might account for the observed preference
of anti over syn aldol product formation.
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realization is the development of a ternary catalyst system
comprised of a chiral pyrrolidine, a carbophilic transition metal
salt, and a Brønsted acid, wherein each component is crucial for
both chemical and stereochemical efficiency. The study
uncovers a new case of chiral enamine catalysis in which a,a-
dialkylprolinol ethers perform better than their parent a,a-
diaryl analogs.18 Given their ready and easy accessibility, this
subclass of amine catalysts may therefore be a good help for
new developments. The present work also demonstrates that
the previously known metal–ynal complexation strategy for
aldol reaction stereocontrol may be made catalytic in metal. We
believe that this latter nding might have further applications
in other (organo)catalytic transformations involving alkynyl
substrates and work in that direction is currently ongoing in
Scheme 3 Catalytic cross-aldol reaction with aromatic aldehydes.
Models for stereochemistry and catalysts action
Intrigued by the fact that a,b-ynals had not been employed our laboratory.
before in enamine mediated aldol reactions, we carried out
control experiments for the reaction between aldehyde 1A and
Acknowledgements
octynal (2a) in the presence of proline,11a a,a-diphenylproli-
nol,11g,k and a,a-bis(3,5-triuoromethyl)phenylprolinol,11g,k Financial support was provided by the University of the Basque
three representative catalysts for aldol reactions. In all cases the Country UPV/EHU (UFI 11/22), the Basque Government (GV
´
corresponding aldol 3Aa was obtained as a nearly equimolar grant No IT-291-07), and the Ministerio de Ciencia e Innovacion
mixture of anti and syn isomers,25 a result that underlines once (MICINN, Grant CTQ2010-21263-C02), Spain. I.O. thanks
again the problem of controlling stereochemistry with a,b- MCINN for a fellowship and I.L. and S.V. thanks UPV/EHU for
ynals. The distinguishing capacity of our catalyst system to grants. We also thank SGIker (UPV/EHU) for providing NMR,
produce anti-congured aldol products would be consistent HRMS and X-Ray resources.
with an open transition state wherein the bulky substituent of
the pyrrolidine ring of the enamine points away from the
alkynyl group of the approaching aldehyde for minimal desta-
Notes and references
bilization (Fig. 3). In this scenario, the Brønsted acid cocatalyst
may play two roles: on the one hand, it may facilitate hydrolysis
of the evolving metal aldolate and iminium groups, thus easing
the recycling of the metal and amine catalysts; on the other
hand, it may enhance the electrophilicity of the aldehyde group
through hydrogen bonding. It may also perform both roles. If
the above model is correct,26 then the observed increase in anti-
selectivity in the presence of a metal cocatalyst might be
explained in terms of steric ination of the alkyne moiety as a
consequence of metal–alkyne association.27
Additional evidence in support of some kind of ynal-specic
complexation to metals28 was obtained from the aldol reactions
involving aromatic instead of alkynyl aldehydes. In these
instances (Scheme 3) the reaction outcome is essentially inde-
pendent of the presence or absence of the metal cocatalyst.
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into stereoselective construction of functionalized propargylic
alcohols. Through this method, adducts bearing two contig-
uous stereogenic centers in very high diastereo- and enantio-
selectivity (anti/syn up to >20 : 1 and ee up to >99%) are
afforded, thus broadening the pool of currently available
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from two dissimilar enolizable aldehydes.23 Key for that
´
´
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5 Representative literature data: ref. 4a (3 examples) 77%–88%
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1 : 1, racemic.
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´
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Chem. Sci.